Fusion of blood vessel organoids with human pancreatic islets improves insulin response over time

Pancreatic islet transplantation is a promising treatment strategy for type 1 diabetes, however there are still major challenges to overcome, including vascularization. Novel strategies for the generation of prevascularized islets with native microvessels have reported improved islet functionality, vascularization and engraftment emphasizing integral role of microvascular bed. Recently a new model of self-organizing three-dimensional human blood vessel organoids (BVOs) has been developed from human pluripotent stem cells (hPSCs), composed of both endothelial and mural cells. BVO recapitulate key features of human microvasculature such as formation of vascular network, vascular lumen and basement membrane, and have been shown to be perfusable. Here, we report a new strategy to construct prevascularized islets by fusion with hPSC-derived BVOs. We demonstrate that islets and BVOs in co-culture leads to fusion and improved insulin secretion over time, on two independent human islet donors, suggesting a new therapeutic approach for pancreatic islet transplantation and type 1 diabetes modeling. ### Competing Interest Statement The authors of this manuscript have no conflicts of interest to disclose as described by BIORXIV. Josef M. Penninger declares a conflict of interest as he is one of the authors of the patent application US20200199541A1 relating to blood vessel organoids generation. Furthermore, J.M. Penninger is founder, shareholder, and chairman of the scientific advisory board of Angios Biotech, a company establishing BVOs for drug testing and vascular transplants. * BMI : body mass index BVO : blood vessel organoid CD31 : cluster of differentiation 31 ELISA : enzyme-linked immunosorbent assay FBS : fetal bovine serum FITC : fluorescein isothiocyanate GSIS : glucose stimulated insulin secretion hiPSC : human induced pluripotent stem cells hPSCs : human pluripotent stem cells LSFM : light sheet florescent microscopy MVF : microvascular fragment PBST : Phosphate Buffered Saline with Tween SI : stimulation index VEGF : vascular endothelial growth factor